Transgender women have among the highest rates of HIV infection, but little is known about HIV prevalence among trans men, Tonia Poteat from Johns Hopkins Bloomberg School of Public Health said in a plenary lecture on transgender health and HIV at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2016)in Boston -- the first ever on this population at CROI. A growing number of studies and prevention and treatment programs are addressing transgender populations, but more research is needed.

Poteat noted that while mainstream knowledge about transgender men and women is relatively new in the U.S. and Europe, largely thanks to celebrities such as Chaz Bono, Laverne Cox, and Caitlyn Jenner, people outside the male-female gender binary have long existed in many cultures, such as the hijra in India.

The size of the transgender population is uncertain, in part due to varying definitions. One estimate put the number of transgender people in the U.S. at approximately 700,000, or 0.3% of the population. Estimates range from 0.1% to 0.5% in Europe, and from 0.7% to 2.9% in South Asia, where some countries legally recognize a "third gender."

Traditional "one-step" data collection approaches can make it difficult to accurately identify trans people in HIV research. Many investigators have categorized study participants according to either their current gender identity or their assigned sex at birth, both of which can result in misclassification. A "two-step" method that asks about both initial sex assignment and current identity is more accurate and inclusive.

"The way you ask the question makes a big difference," Poteat stressed.

For example, the international iPrEx trial of tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis (PrEP) included transgender women in its population of 2499 men who have sex with men. The initial published iPrEx report said the study included just 29 trans women, but a later analysis used a broader definition -- including people assigned male at birth who identified as women, trans, or "travesty," and those who identified as men but used feminizing hormones -- bringing the total up to 339.

HIV Rates in Trans Populations

As Susan Buchbinder from the San Francisco Department of Public Health said in her introduction to the lecture, "There is probably no population that is both more heavily impacted [by HIV] and less discussed around the world than transgender people."

Poteat said that very little is known about HIV rates among transgender men. A recent systematic review found 6 U.S. studies, including a self-report study with a prevalence of 0.4% and 5 studies based on laboratory testing with rates ranging from 0.5% to 4.3%, but actual numbers were small. Among non-U.S. studies, 3 based on self-report found prevalence rates of 0.6% to 0.8%, while 2 based on lab tests had rates of 0% and 2.2%.

A bit more is known about trans women, who were the main focus of Poteat's talk. Trans women who have sex with men have one of the highest burdens of HIV infection among key affected populations, which also include gay and bisexual men and people who inject drugs.

One worldwide meta-analysis of 39 studies from 15 countries found that transgender women had an HIV prevalence rate of 19% -- 49 times higher than that of the general population. In high-income countries, the prevalence was 22%, with the highest rate among trans women of color.

A more recent meta-analysis by Poteat's group looked at 49 new studies, which showed both an exponential increase in research and an ongoing high burden of HIV infection. Among the included studies based on lab testing, prevalence rates ranged from 2% among trans youth to 45% among trans sex workers. The 3 studies that estimated incidence, or new infections, reported rates of 1.2 to 3.6 per 100 person-years.

Even in countries where HIV prevalence in the general population is high, trans women still face a disproportionate burden. In Lesotho, for example, overall prevalence is estimated at 18% for all cisgender (non-transgender) men, 27% for all cisgender women, and 28% for men who have sex with men, but rises to 60% for trans women.

Vulnerabilities Affecting Trans People

A number of factors may make transgender people more susceptible to HIV infection or less likely to use prevention methods or access treatment if they become infected.

Biological factors include hormone therapy, which has the potential to interact with PrEP or antiretroviral treatment (ART). While no clinically significant interactions have been confirmed between feminizing hormones and tenofovir/emtricitabine PrEP or most antiretrovirals, many trans women worry about them and prioritize hormone use.

To date, no randomized clinical trials have looked specifically at PrEP for transgender women, but an iPrEx substudy led by Madeline Deutsch from the University of California at San Francisco's Center of Excellence for Transgender Health found that Truvada appeared to protect trans women who took it consistently. No seroconversions occurred among trans women with tenofovir drug levels indicating they took at least 4 pills per week. However, their level of adherence was lower than that of gay men in the study, which Deutsch suggested could be due to concerns about PrEP and hormone interactions.

Prior studies have shown that tenofovir reaches higher levels in rectal tissue in men than in cervical or vaginal tissue in women. This could in part be related to hormonal differences between cisgender men and women, although some have found that tenofovir levels are lower in cervical-vaginal tissue samples than in matched rectal tissue samples obtained from the same women.

Some researchers hypothesize that exogenous or administered estrogen may affect tenofovir pharmacokinetics, for example by interfering with creatine kinase phosphorylation of tenofovir disoproxil fumarate to its active form of tenofovir diphosphate. This could mean that trans women taking estrogen and PrEP will have lower tenofovir levels in rectal tissue than cisgender men, and therefore may need higher doses -- a prospect that requires further study.

Hormones could also potentially cause changes in rectal or vaginal mucosa that increase susceptibility to HIV. Further, sharing needles to inject hormones or fillers such as silicone can transmit HIV and hepatitis B or C. It is not know whether trans women who have genital sex reassignment or affirmation surgery are more vulnerable to HIV infection.

Social and Structural Factors

Social and structural factors that increase trans people's vulnerability to HIV include stigma, fear of disclosure, sexual networks that include more HIV-positive people, poverty, lack of employment opportunities which leads many trans women to engage in sex work, homelessness or unstable housing, violence, lack of access to health care or insurance, substance use, and mental health issues such as depression.

Although many transgender women are eligible for PrEP according to U.S. Centers for Disease Control and Prevention or World Health Organization guidelines, most are not yet using it and may not be aware of it. One study found that only about 14% of trans women in San Francisco -- a city were PrEP awareness and use among gay and bi men are high -- had heard of PrEP at the end of 2013.

Poteat reported that among people with HIV using Ryan White HIV/AIDS services, transgender people were less likely than patients overall to remain in care (78% vs 80%) and to achieve viral suppression (74% vs 81%).

A survey of HIV-positive trans women conducted by the Transgender Law Center found that gender-affirming care and hormone therapy were their top priority, considered more urgent than HIV treatment. But trans women who had the same provider for both hormone therapy and HIV treatment were more likely to stay in care and have an undetectable viral load, demonstrating the benefit of integrated care.

"Transgender women have disproportionate HIV prevalence and incidence due to the interplay of biological and intersectional social factors," Poteat concluded. "Gender-affirming approaches are necessary to achieve optimal outcomes."

To address barriers to care for trans women it is important to "reduce stigma and prevent secondary trauma including racism, transphobia, economic disadvantage, and other structural factors," she said. "HIV services we have available, mostly geared towards gay men, do not meet the needs of trans women."